title: The Gdac1 locus modifies spontaneous and Salmonella-induced colitis in mice deficient in either Gpx2 or Gpx1 gene.
abstract: We previously identified the Gdac1 (Gpx-deficiency-associated colitis 1) locus, which influences the severity of spontaneous colitis in Gpx1- and Gpx2-double-knockout (Gpx1/2-DKO) mice. Congenic Gpx1/2-DKO mice in the 129S1/SvImJ (129) background but carrying the Gdac1(B6) allele have milder spontaneous colitis than 129 Gpx1/2-DKO mice carrying the Gdac1(129) allele. Here, we evaluated the effect of the Gdac1(B6) allele on 129 strain non-DKO mice that had a wild-type (WT) Gpx1 or Gpx2 allele and WT mice. We found that the congenic Gdac1(B6) Gpx2-KO, Gpx1-KO, and WT mice also had better health than the corresponding 129 mice measured by at least one of the parameters including disease signs, colon length, or weight gain. The Gdac1(B6) allele prevented loss of goblet cells and crypt epithelium exfoliation in the Gpx1/2-DKO mice, but did not affect epithelial cell apoptosis or proliferation. Because Gdac1(B6) affects gut dysbiosis in the DKO mice, we then tested its impact on bacteria-induced colitis in non-DKO mice. First, we found both Gpx1-KO and Gpx2-KO mice were susceptible to Salmonella enterica serotype typhimurium (S. Tm)-induced colitis under conditions where WT B6 and 129 mice were resistant. Second, the S. Tm-infected Gdac1(B6) Gpx1-KO mice had stronger inflammatory responses than 129 Gpx1-KO or 129 Gpx2-KO with both Gdac1 alleles and WT mice by having higher mRNA levels of Nod2, Nox2, Tnf, and Cox2. We conclude that the Gdac1 locus affects both spontaneous and S. Tm-induced colitis in 129 non-DKO mice, although in opposite directions.
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: R
authors.initials: R
authors.lastname: Steven Esworthy
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Byung-Wook
authors.initials: BW
authors.lastname: Kim
authors.affiliation: Department of Gastroenterology and Hepatology, First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan 471000, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan 471000, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.affiliation: National Cancer Institute, Bethesda, MD 20816, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Leto
authors.affiliation: Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. Electronic address: fchu@coh.org.
authors.forename: Fong-Fong
authors.initials: FF
authors.lastname: Chu
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D003092:Colitis / Q000235:genetics* / Q000382:microbiology; D051546:Cyclooxygenase 2 / Q000235:genetics; D064806:Dysbiosis / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D014644:Genetic Variation; D005979:Glutathione Peroxidase / Q000235:genetics*; D020397:Goblet Cells / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000235:genetics; D008795:Metronidazole / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012480:Salmonella Infections / Q000188:drug therapy / Q000276:immunology*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
chemical_list: D008562:Membrane Glycoproteins; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D008795:Metronidazole; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000094765:Glutathione Peroxidase GPX1
keywords: DUOX2; Free radicals; GPX-deficiency-associated-colitis locus-1; GPX1; GPX2; Gdac1; Gut dysbiosis; Metronidazole; Mouse genetics; Salmonella enterica serotype typhimurium; Selenium